3alpha, 11beta dihydroxy-11alpha-lower alkyl-5beta-pregnan-20-one 3-hemisuccinate, its salts, and buffered preparation thereof



Patented July 4, 1961 Upjohn Company, Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed May 13, 1959, Ser. No. 812,815

4 Claims. (Cl. 167-52) This invention relates to novel steroid compounds and, more particularly, to 3a,llB-dihydroxy-lla-lower-alkyl- 5fl-pregnan-20-one B-hemisuccinate and alkali metal salts thereof.

This application is a continuation-in-part of copending application Serial No. 661,036, filed May 23, 1957, now Patent No. 2,944,069. 7

The compounds of this invention are useful for their sedative and analgetic properties as well as in the treatment of hypertension, nervous disorders and related illnesses and are characterized by pronounced central nervous system depressant activity. Because of the water solubility of the said compounds their high potency can be utilized eflicaciously by intravenous or intramuscular administration to afford an early response in the patient and to provide a means for treating patients incapable of accepting medication by the oral route. I

The preparation of the novel compounds of this invention can be represented in the following sequence of reactions:

C Hz CH3 $113 CH3 C=ketal C=ketal lower all yl of HO CH OH H H O I II 0 Ha CH3 CH OH;

O lower alkyl lower alkyl no HO CH CH,

C H2 0 O O H O HFfi/"O HO IV III CH: 0:.- lower alkyl GHQ-C O OM C Hg-(fi -O 0 wherein, the lower alkyl radical contains from one to eight carbon atoms, inclusive, e.g., methyi, ethyl, propyl, butyl, pentyl, hexyl, isohexyl, heptyl, 'octyl, isoheptyl, etc., and M is an alkali metal, such as sodium, potassium, lithium, and the like.

The novel 3a,].IB-dlhYdl'OXY-l1oc-l0W6I'all(yi-5flp1'egnan--one 3-hemisuccinate can be prepared by alkylating 3a-hydroxy-5/3-pregnane-l1,20-dione 20-keta1 (I) [J. Org. Chem. 17:290 (1952)] with an alkyl metal compound to give 3a,1 lfl-dihydroxy-l 1a-lower-alkyl-5p-pregnan-20-one ZO-ketal (II). The said ZO-ketal is then hydrolyzed to produce 3a,11/3-dihydroxy 11a lower-alkyl-Sfi-pregnam 20-one (III), which is then reacted with succinic anhydride to yield 3a,1LB-dihydroxy-llot-lower alkyl-5fi-pregnan-20-one 3-hemisuccinate (IV). The alkali metal salts of the said S-hemisuccinate are then prepared by neutrali- The alkylation step of the present process, i.e., the conversion of the starting ll-keto compound (I) to the 11mlower-alkyl-l lfl-hydroxy compound (II), is accomplished by reaction of the starting 3a-hydroxy-5p-pregnane-ll, 20-dione 20-ketal (I) with a lower alkyllithium, e.g., methyl, ethyl, propyl, butyl, isobutyl, amyl, hexyl, heptyl, octyl, etc. lithium, with methyllithium being preferred. The usual prior art reaction conditions for alkylation of a carbonyl group with an alkyllithium can be employed. Normally the present alkylation is carried out at about room temperature, i.e., between about 1535 C., without heating or cooling. However, the process is operative at somewhat higher and lower temperatures. The intermediate lla-lower-alkyl-llfl-hydroxy-lithium complex is decomposed with water, acid, methanol, ethanol, etc., according to known methods, to produce the desired 30:,115- dihydroxy-l lot-lower-alkyl 5 p pregnan-ZO-one ZO-ketal The hydrolysis step of the present process involves'the cleavage of the 20-ketal steroid to regenerate 312,1 lfi-dihydroxy-l1a-lower-alkyl-5 3-pregnan-20-one (III). The ketal is dissolved in an organic solvent, and the resulting solution is admixed with at least a theoretical amount, and preferably an excess, of water or an acid as the hydrolyzing agent. The organic solvent is preferably of the watermiscible type, such as acetone, methanol, ethanol, dioxane, etc. Ordinarily, it is preferred that a temperature of about 20-40 C. be employed for the reaction, but temperatures as low as zero and as high as C. are operative. The time required for the reaction can be varied between about 1-24 hours, depending on the temperature and hydrolyzing agent employed. Likewise, the amount of acid can be varied over a wide range, amounts from a trace to a large excess being operative. Suitable hydrolyzing agents include strong acids such as, for example, sulfuric acid, hydrochloric acid, orthoor paratoluenesulfom'c acid, naphthalenesulfonic acid, benzenesulfonic acid, ortho-chlorobenzenesulfonic acid, trichloroacetic acid, or the like, sulfuric acid or hydrochloric acid being preferred. The acid hydrolyzing agent is generally employed as a dilute aqueous solution, concentrations in the reaction mixture of about 0.l%20% being preferred.

The 302,1 1 B-dihydroxy-l 1a-lower alkyl-5 9-pregnan-20- one 3-hemisuccinate (IV) is conveniently prepared byfaction of the said 3u,llfi-dihydroxy-11a-lower-alky1-5 S- pregnan-ZO-one (III) with succinic anhydride in a mutual solvent such as pyridine or lutidine, permitting the reaction to proceed for several hours. The product ester is recovered from the reaction mixture, for example, by adding a precipitating agent to bring down the 3-hemisuccinate as the free-acid ester or a salt thereof. An aqueous solution of hydrochloric acid or other strong mineral acid can be used when pyridine or like organic bases are employed as the mutual solvent. Ordinarily it is sufiicient to pour the reaction mixture slowly into an excess of dilute aqueous hydrochloric acid and then filter ofiithe precipitated product. The product canthen be further purified by crystallization from a polar solventsuch as acetone, methyl ethyl ketone, ethanol, isopropanol, p3- ethoxyethanol, ethyl acetate and mixtures of thesame with Skellysolve B (hexane hydrocarbons), ether, and water where the resulting solvent system is homogeneous.

The thus-produced 3a,1lfi-dihydroxy-lla-lower-alkyl- Sfi-pregnan-ZO-one 3-hemisuccinate can then be converted to a salt by neutralization with the appropriate base. Suitable bases are the alkali metal hydroxides and carbonates, such as sodium, potassium or lithium hydroxide or carbonate. The free acid ester is dissolved in a volatile water-miscible solvent, such as acetone, and the solution neutralized by adding aqueous alkali or alcoholic alkali. Other suitable volatile water-miscible solvents include methanol, ethanol isopropanol. The solvents are then removed by vacuum distillation. Advantageously, the water can also be removed by lyophilization. Before lyophilization the water solution is filter-sterilized where a sterile produce is desired. A bufiered preparation containing the alkali metal salts can be readily prepared by neutralizing the product to pH 7 with a buffering agent, such as trisodium phosphate dodecahydrate.

The examples which follow are illustrative of the process yielding the productsof the present invention but are not to be construed as limiting the scope thereof.

Example 1.--3a,1]B-dihydr0xy-11 a-methyI-SB-pregnan- 20-0ne ZO-ethylene ketal (II) A solution of 13.6 gm. of 3a-hydroxy-5B-pregnane-11, 20-dione 20-ethylene ketal (I) in 150 ml. of benzene and 100 ml. of ether was treated with 144 ml. of molar ethereal methyllithium at room temperature overnight. The resulting solution was washed twice with water, filtered through sodium sulfate, and evaporated to dryness at reduced pressure. Chromatographic separation yielded 30:, llp-dihydroxy-l Ia-methyl-Sfl-pregnan-ZO-One 20-ethylene ketal (II) as an oil.

If for the methyllithium employed above there is substituted another lower-alkyllithium, e.g., ethyl-, propyl-, butyl-, isobutyl-, amyl-, hexyl-, heptyl-, octyl-, etc., the corresponding ll-alkylated steroids are produced.

Example 2.3u,I1fi-dihydr0xy-1Ia-methyI-SB-pregnan- 20-one (III) V The 3a,1 118 dihydroxy-l1a-methyI-SrLpIegnan-ZO-one 20-ethylene ketal from Example 1 was dissolved. in 200. ml. of methanol and treated with 10 ml. of 3. N sulfuric acid at room temperature for 28 hours. Addition of 200 ml. of water and cooling in a refrigerator overnight produced a gel which, on standing at room temperature, gave 6.74 gm. of crystalline solid melting at 149-168 C. Repeated recrystallization from acetone-Skellysolve B. hexanes yielded 0.22 gm. of pure 3a,11}8-dihydroxy-11otmethyl-5p-pregnan-20-one (III), melting at 184-l86. C. and having [a] +111 (acetone).

Analysis.-Calcd. for C H O C, 75.81; H, 10.41. Found: C, 75.43; H, 10.25.

Substitution of other ll-alkylated ketals, in which the alkyl group is lower alkyl as indicated in Example 1, as the starting material herein is productive of the corresponding 311,115 dihydroxy-l1a-lower-alkyl-5/8-pregnan- 20 -one.

Example 3.-3a,]1B-dihydr0xy-1Ia-methyI-SB-pregnan- 20-0ne 3-hemisuccinate (IV) A mixture of 6.6 gm. of 3a,1l/3-dihydroxy-1lot-methyl- Sfl-pregnan-ZO-on (III), 6.6 gm. of succinic'anhydride and 60 ml. of pyridine was refluxed for 21 hours andithen poured over crushed ice. After the ice had melted,' the: product was recovered by filtration and 'washe'd with:

-ample 1, is productive of the corresponding 3a,llfi-dihydroxy-lla-lowepalkyl 5 pi pregnan -20-one 3-hernisuccinate.

Example 4.-Sodium 3a,1lB-dihydr0xy-11a-methyl-SB- pregnan-ZO-one 3-succinate (V) A mixture is prepared by warming 5.0 gm. of 311,115- dihydroxy-l1a-methyl-5;3-pregnan-20-one 3-hemisurxinate (IV) in 20 ml. of acetone and cooling to room temperature. With continuous stirring, 20 ml. of 0.5 N aqueous sodium hydroxide is added gradually over a period of 10 minutes. The pH is maintained below 7.5, and the end point adjustment is made by adding in divided portions 0.5 N aqueous sodium hydroxide until a pH of 7.2-7.4 is obtained. The reaction mixture is then concentrated to. about 25 ml. in an atmosphere of nitrogen and under vacuum. The pot temperature should not exceed about 26 C. The concentrate is then treated with 2 gm. of diatomaceous earth, filter sterilized and lyophilized to give essentially pure sodium 3a,11fl-dihydroxy-1 la'methyl-Sfl-pregnan-ZO-one 3-suocinate.

Substitution of other ll-alkylated hemisuccinates, in which the alkyl group is lower alkyl as indicated in Example 1, for the starting material herein is productive,

of the corresponding 3a,11B-dihydroxy-llwlower-alkyl- 5B-pregnan-20-one 3-succinate.

Example 5.Bufiered sodium 3a,1l;3'dihydroxy-11amethyl-Sfl-pregnan-ZO-one 3-succinate A mixture is prepared by mixing 5.2 gm. of 3a,11fi-dihydroxy-l1a-methyl-5fl-pregnan-20-one S-hemisuccinate and 3.1 gm. of trisodium phosphate dodecahydrate in ml. of water' for 30minutes. The resulting mixture is sterilized by filtration through a Seitz filter and lyophilized to give 7.0 gm. of a sterile, flufly solid comprising a mixture of sodium 311,1lfi-dihydroxy-l1a-methyl-5fl-pregnan- 20-one 3-succinate, disodium hydrogen phosphate and sodium dihydrogen phosphate. This material can then be reconstituted with sterile aqueous diluent for intravenous or intramuscular use.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art; the invention is therefore to be limited only by the scope of the appended claims.

What is claimed is:

1. A compound selected from the group consisting of 3a,11/3 dihydroxy-l1alower-alkyl-Sfi-pregnanQO-one 3- hemisuccinate and the alkali metal salts thereof.

2. 30:,11B-dihYdI0XY 11a methyl-Sfl-pregnan-ZO-one 3-hemisuccinate.

3. Sodium 3a,11}3 dihydroxy-l1u-methyl-5fi-pregnan- 20-one 3-hemisuccinate.

4. A coprecipitated combination comprising 3a,llf3-di hydroxy-l1a-methyI-SB- regnan-ZO-one 3-hemisuccinate neutralized to pH 7 with trisodium phosphate dodccahydrate.

Federal Register, p. 9516, 21 C.R.F. 8121.100, 167/ 65MU (December 9, 1958). 

4. A COPERCIPITATED COMBINATION COMPRISING 3A,11B-DI HYDROXY-11A-METHYL-5B-PREGNAN-20-ONE 3-HEMISUCCINATE NEUTRALIZED TO PH 7 WITH TRISODIUM PHOSPHATE DODECAHYDRATE. 